- Email: [email protected]
Revealing the Genetic Instructions for Nervous System Wiring
Interestingly, however, it is fairly difficult for humans to behave randomly. One strategy that might overcome this problem is to rely on stochastic noise, which is present in the brain, as in all biological systems. Schurger and colleagues [15], for instance, suggest that, given a weak imperative to move, the precise moment at which the decision threshold for movement is crossed is largely determined by spontaneous fluctuations in neuronal activity. Is it possible that people can somehow take account of such fluctuations and use them to generate ‘spontaneous’ actions? In this case, the observation that brain activity precedes the conscious ‘urge to act’ would no longer be inconsistent with our beliefs about the nature of volition.
involuntary actions and effects. Conscious. Cogn. 21, 501–506 7. Moretto, G. et al. (2011) Experience of agency and sense of responsibility. Conscious. Cogn. 20, 1847–1854 8. Brass, M. et al. (2013) Imaging volition: what the brain can tell us about the will. Exp. Brain Res. 229, 301–312 9. Schlegel, A. et al. (2013) Barking up the wrong free: readiness potentials reflect processes independent of conscious will. Exp. Brain Res. 229, 329–335 10. Matsuhashi, M. and Hallett, M. (2008) The timing of the conscious intention to move. Eur. J. Neurosci. 28, 2344–2351 11. Frith, C.D. (2000) The role of dorsolateral prefrontal cortex in the selection of action as revealed by functional imaging. In Control of Cognitive Processes (Monsell, S. and Driver, J., eds), pp. 549–565, MIT press 12. Frith, C. (2013) The psychology of volition. Exp. Brain Res. 229, 289–299 13. Rolnick, J. and Parvizi, J. (2011) Automatisms: bridging clinical neurology with criminal law. Epilepsy Behav. 20, 423–427 14. Fehr, E. and Gächter, S. (2002) Altruistic punishment in humans. Nature 415, 137–140 15. Schurger, A. et al. (2012) An accumulator model for spontaneous neural activity prior to self-initiated movement. Proc. Natl. Acad. Sci. U. S. A. 109, E2904–E2913
Acknowledgements P.H. is supported by a grant from the Leverhulme
eventually find and connect with their appropriate targets. Also, in complex nervous systems like the human brain, this process somehow has to be coordinated for billions of neurons, by a program encoded in the genome. In the early 1990s, some of the basic mechanisms by which growing axons are guided had been worked out but the molecules involved were largely unknown. Painstaking work in a variety of model systems had revealed that growing axons respond to surface-bound and diffusible cues from surrounding cells, that such cues can be either attractive or repulsive for specific axons, that axons navigate using a series of intermediate targets, and that they selectively fasciculate with each other based on their respective repertoires of adhesion molecules.
Trust (RPG-2016-378), by European Research Council (ERC) advanced grant HUMVOL (agreement 323943), and by a Chaire Blaise Pascal of the Région
Series: Seminal Neuroscience Papers 1978–2017
Île-de-France. 1
Institute of Philosophy, University of London, Senate House, Malet Street, London WC1E 7HU, UK 2 Wellcome Centre for Human Neuroimaging at University College London, 12 Queen Square, London WC1N 3BG, UK 3
Institute of Cognitive Neuroscience at University College London, 17 Queen Square, London WC1N 3AR, UK 4 Laboratoire de Neurosciences Cognitives, Département d’Études Cognitives, École Normale Supérieure, 29 Rue d’Ulm, Paris 75005, France *Correspondence: [email protected] (C.D. Frith) and [email protected] (P. Haggard). https://doi.org/10.1016/j.tins.2018.04.009 References 1. Libet, B. et al. (1983) Time of conscious intention to act in relation to onset of cerebral activity (readiness-potential). The unconscious initiation of a freely voluntary act. Brain 106, 623–642 2. Dennett, D.C. and Kinsbourne, M. (1992) Time and the observer: the where and when of consciousness in the brain. Behav. Brain Sci. 15, 183–201 3. Haggard, P. and Eimer, M. (1999) On the relation between brain potentials and the awareness of voluntary movements. Exp. Brain Res. 126, 128–133 4. Shepherd, J. (2012) Free will and consciousness: experimental studies. Conscious. Cogn. 21, 915–927 5. Hart, H.L.A. (2008) Punishment and Responsibility: Essays in the Philosophy of Law, Oxford University Press 6. Dogge, M. et al. (2012) When moving without volition: implied self-causation enhances binding strength between
Science & Society
Revealing the Genetic Instructions for Nervous System Wiring Kevin J. Mitchell1,*,@
Many of the underlying principles were elucidated by Corey Goodman and his colleagues, using the simple nervous systems of grasshopper and fruit fly embryos as models. The embryonic ventral nerve cord of these species is bilaterally symmetric and segmentally repeated, comprising about 200 neurons in each hemisegment. Early work led by Goodman and Michael Bate described the origins and projection patterns of many of these neurons [1]. Further studies using electron microscopy, immunohistochemistry, and targeted cell ablation highlighted the roles in guiding growing axons of cellular interactions with specialised glial cells or with previously projecting axons [2–4].
Why did the axon cross the midline? A 1993 paper by Corey Goodman and colleagues described a genetic screen in fruit flies that pioneered the discovery of conserved families of axon guidance cues and receptors, highlighting fundamental pro- The Midline Screen cesses underlying wiring specificity All of this work laid the foundation for a in the developing nervous system. genetic screen to try to identify the molecGuiding Growing Axons Growing neurons face a daunting task: they must extend their axon along a predefined trajectory through the complex terrain of the developing nervous system, navigating a series of choice points, to
ular cues that guide growing axons and the receptors that determine their responses [5]. This idea was directly inspired by the tremendous success of the genetic screens conducted by Christiane Nüsslein-Volhard and Eric Wieschaus, which had discovered so many of the
Trends in Neurosciences, July 2018, Vol. 41, No. 7
407
fundamental molecules and mechanisms across the genome. These random mutaunderlying early patterning of the fruit fly tions were captured in separate lines by crossing in specific ‘balancer’ chromoembryo [6]. somes that prevent recombination. The The concept behind the screen was to try embryonic progeny derived from interto find genes influencing one simple guid- crossing each line could then be examance decision: whether axons project ined with the expectation that one-quarter across the midline of the ventral nerve cord. of them would be homozygous for the About 90% of neurons in each segment mutant chromosome. This approach tarnormally send an axon across the midline in geted genes on the X chromosome and one of two commissures. These axons on chromosomes 2 and 3, which collecthen make a 90-degree turn to head ante- tively comprise most of the fly genome. riorly or posteriorly in a large longitudinal bundle. The other 10% of axons never Hundreds of mutant lines were recovered cross the midline and just project in the showing defects in the pattern of axonal longitudinal on the same side as their cell projections. These fell into a number of body. The resulting pattern of axons categories, some affecting the longitudiresembles a ladder. Crucially, this pattern nal tracts, others affecting the commiscould be robustly visualised in whole- sures crossing the midline, each in a mount embryos with a specific antibody number of different ways. Through (Figure 1) and even subtle derangements genetic mapping and complementation, from the normal pattern could be detected it was possible to assign different mutations to different genes. The fact that mulunder the dissecting microscope. tiple mutations in individual genes were Mark Seeger, Guy Tear, and Dolores Fer- recovered provided evidence that the res-Marco established over 13 500 screen had achieved saturation: all of mutant lines using a chemical mutagen the genes that could be mutated to give that induces point mutations at random viable embryos with a visible axonal
(A)
(B)
(C)
phenotype had indeed been mutated and screened. The goal of the screen was to identify genes encoding axon guidance cues and receptors, and several were found. However, mutations affecting many other processes, such as embryonic patterning, neurogenesis, or cell fate, can also indirectly result in an aberrant axonal scaffold. A crucial factor in the success of the screen was the ability to analyse mutant lines with a series of other antibodies, revealing defects in these earlier processes in many lines, which could then be excluded from detailed follow up.
Conserved Axon Guidance Molecules Of the mutations with apparently direct effects on axon guidance, two stood out for their specific and reciprocal effects on midline crossing (Figure 1). Mutations in commissureless (comm) resulted in the complete failure of axons to cross the midline. All of the neurons were present and extended axons, but only on their own side, resulting in a ladder with no rungs. Conversely, mutations in roundabout (robo) caused all axons to cross the midline, and not just once: many axons recrossed the midline repeatedly.
These phenotypes suggested that comm might encode a component of an attractive S system, necessary for axons to cross the PC midline, while robo might encode a comIS L ponent of a repulsive system that prevents inappropriate crossing or recrossing. However, double-mutant analysis suggested an alternative model. Double comm;robo mutants look like robo single mutants. Thus, in the absence of robo, removal of comm has no effect: axons can still cross the midline. This suggested that the funcFigure 1. Mutations in commissureless (comm) and roundabout (robo) Disrupt Midline Crossing. tion of the Comm protein might be to The complete axonal scaffold of the Drosophila embryonic ventral nerve cord can be visualised with the antibody repress the Robo system. AC
BP102. (A) Several segments are shown, highlighting the anterior (AC) and posterior (PC) commissures, the longitudinal tracts (L), and the segmental (S) and intersegmental (IS) nerves connecting the central nervous system to the periphery. (B) Phenotype of a comm mutant, where no axons cross the midline. (C) Phenotype of a robo mutant, where all axons cross and recross the midline. Reprinted, with permission, from [5].
408
Trends in Neurosciences, July 2018, Vol. 41, No. 7
When these genes were cloned a few years later, this prediction was borne
out. robo encodes a transmembrane protein of the immunoglobulin superfamily [7]. It was later shown to be one of a trio of related receptors for the secreted protein Slit, which is expressed by specialised glial cells at the midline [8,9]. slit mutations, which were also recovered in the screen, have an even more severe phenotype than robo mutations because of redundancy between robo-1, -2, and -3. Both the Robo and the Slit families are highly conserved and play major roles in axon guidance not just at the midline but in many areas of the developing nervous system, including in the human brain. comm encodes a protein expressed in the endoplasmic reticulum that controls the trafficking of the Robo protein to the cell surface [10]. The selective early expression of Comm in just those neurons that normally cross the midline determines which neurons cross the midline and which do not [11]. This system also dynamically regulates axonal responsiveness, so that axons that have crossed the midline upregulate Robo and subsequently are repelled away from it, ensuring that they only cross once. Recent results from the laboratory of Tom Kidd show that Comm also has an orthologue with similar molecular functions in mammals, mutations in which are implicated in neurological disease [12]. These proteins are all involved in repulsive signalling from the midline but what about attraction? Why do axons head towards the midline in the first place? This similarly depends on a conserved set of molecules: netrins and their receptors of the Unc-40/DCC and Unc-5 families, first discovered in worms [13] and subsequently in vertebrates and flies [14]. Mutations in Netrin genes were not recovered in the midline screen because there are two of them and they act redundantly to attract axons towards the midline. However, mutations in the Unc-40/DCC family receptor, called frazzled in flies, were
identified in the screen, and independently in the laboratory of Yuh-Nung and Lily Jan. These mutations result in fewer axons crossing the midline [15].
11. Keleman, K. (2002) Comm sorts Robo to control axon guidance at the Drosophila midline. Cell 110, 415–427 12. Justice, E.D. (2017) The WAGR syndrome gene PRRG4 is a functional homologue of the commissureless axon guidance gene. PLoS Genet. 13, e1006865 13. Hedgecock, E.M. et al. (1990) The unc-5, unc-6, and unc40 genes guide circumferential migrations of pioneer axons and mesodermal cells on the epidermis in C. elegans. Neuron 4, 61–85
The paper by Seeger et al. helped to pioneer the molecular identification of 14. Davies, A.M. (1994) Neural development. Chemoattractants for navigating axons. Curr. Biol. 4, 1142–1145 axon guidance cues and receptors, most P.A. et al. (1996) frazzled encodes a Drosophila of which were found to be highly con- 15. Kolodziej, member of the DCC immunoglobulin subfamily and is served. In the process it also illustrated required for CNS and motor axon guidance. Cell 87, 197–204 several fundamental principles of general importance. It stands out for the many years of careful descriptive work that preceded it, which laid the foundation for a Series: Seminal Neuroscience Papers genetic screen. In addition, it is testament to the idea that if you know enough about 1978–2017 the system you are investigating, you can let the organism tell you what the under- Science & Society lying processes and important molecules are.
Brain Perfusion and Astrocytes
1 ?[87_TD$IF]?Smurfit Institute of Genetics and Institute of Neuroscience, Trinity College Dublin, Dublin 2, Ireland
*Correspondence: [email protected] (K.J. Mitchell). https://doi.org/10.1016/j.tins.2018.04.008 References 1. Thomas, J.B. et al. (1984) From grasshopper to Drosophila: a common plan for neuronal development. Nature 310, 203–207 2. Goodman, C.S. et al. (1984) Cell recognition during neuronal development. Science 225, 1271–1279 3. Jacobs, J.R. and Goodman, C.S. (1989) Embryonic development of axon pathways in the Drosophila CNS. I. A glial scaffold appears before the first growth cones. J. Neurosci. 9, 2402–2411 4. Klämbt, C. et al. (1991) The midline of the Drosophila central nervous system: a model for the genetic analysis of cell fate, cell migration, and growth cone guidance. Cell 64, 801–815 5. Seeger, M. et al. (1993) Mutations affecting growth cone?guidance in Drosophila: genes necessary for guidance toward or away from the midline. Neuron 10, 409– 426 6. Nüsslein-Volhard, C. and Wieschaus, E. (1980) Mutations affecting segment number and polarity in Drosophila. Nature 287, 795–801 7. Kidd, T. et al. (1998) Roundabout controls axon crossing of the CNS midline and defines a novel subfamily of evolutionarily conserved guidance receptors. Cell 92, 205–215 8. Kidd, T. et al. (1999) Slit is the midline repellent for the Robo receptor in Drosophila. Cell 96, 785–794 9. Brose, K. et al. (1999) Slit proteins bind Robo receptors and have an evolutionarily conserved role in repulsive axon guidance. Cell 96, 795–806 10. Tear, G. et al. (1996) commissureless controls growth cone guidance across the CNS midline in Drosophila and encodes a novel membrane protein. Neuron 16, 501–514
Bruno Cauli1,* and Edith Hamel2,* How can blood rapidly and precisely reach active neurons at a given time and location has remained enigmatic for a long time. A 2003 paper by Zonta et al. suggested key roles for astrocytes in the signaling between neurons and blood vessels. While a consensus on the specific intermediary roles of astrocytes in this process is still evolving, research in the past 15 years has led to a deeper and more refined understanding of the neuro-glio-vascular unit. The brain is an energy-consuming organ that depends on constant glucose and oxygen supply from the blood. The relationship between neuronal activity and local increases in cerebral blood flow, referred to as neurovascular coupling (NVC), was recognized more than a century ago. It is generally considered so precise that modern brain imaging Trends in Neurosciences, July 2018, Vol. 41, No. 7
409
involuntary actions and effects. Conscious. Cogn. 21, 501–506 7. Moretto, G. et al. (2011) Experience of agency and sense of responsibility. Conscious. Cogn. 20, 1847–1854 8. Brass, M. et al. (2013) Imaging volition: what the brain can tell us about the will. Exp. Brain Res. 229, 301–312 9. Schlegel, A. et al. (2013) Barking up the wrong free: readiness potentials reflect processes independent of conscious will. Exp. Brain Res. 229, 329–335 10. Matsuhashi, M. and Hallett, M. (2008) The timing of the conscious intention to move. Eur. J. Neurosci. 28, 2344–2351 11. Frith, C.D. (2000) The role of dorsolateral prefrontal cortex in the selection of action as revealed by functional imaging. In Control of Cognitive Processes (Monsell, S. and Driver, J., eds), pp. 549–565, MIT press 12. Frith, C. (2013) The psychology of volition. Exp. Brain Res. 229, 289–299 13. Rolnick, J. and Parvizi, J. (2011) Automatisms: bridging clinical neurology with criminal law. Epilepsy Behav. 20, 423–427 14. Fehr, E. and Gächter, S. (2002) Altruistic punishment in humans. Nature 415, 137–140 15. Schurger, A. et al. (2012) An accumulator model for spontaneous neural activity prior to self-initiated movement. Proc. Natl. Acad. Sci. U. S. A. 109, E2904–E2913
Acknowledgements P.H. is supported by a grant from the Leverhulme
eventually find and connect with their appropriate targets. Also, in complex nervous systems like the human brain, this process somehow has to be coordinated for billions of neurons, by a program encoded in the genome. In the early 1990s, some of the basic mechanisms by which growing axons are guided had been worked out but the molecules involved were largely unknown. Painstaking work in a variety of model systems had revealed that growing axons respond to surface-bound and diffusible cues from surrounding cells, that such cues can be either attractive or repulsive for specific axons, that axons navigate using a series of intermediate targets, and that they selectively fasciculate with each other based on their respective repertoires of adhesion molecules.
Trust (RPG-2016-378), by European Research Council (ERC) advanced grant HUMVOL (agreement 323943), and by a Chaire Blaise Pascal of the Région
Series: Seminal Neuroscience Papers 1978–2017
Île-de-France. 1
Institute of Philosophy, University of London, Senate House, Malet Street, London WC1E 7HU, UK 2 Wellcome Centre for Human Neuroimaging at University College London, 12 Queen Square, London WC1N 3BG, UK 3
Institute of Cognitive Neuroscience at University College London, 17 Queen Square, London WC1N 3AR, UK 4 Laboratoire de Neurosciences Cognitives, Département d’Études Cognitives, École Normale Supérieure, 29 Rue d’Ulm, Paris 75005, France *Correspondence: [email protected] (C.D. Frith) and [email protected] (P. Haggard). https://doi.org/10.1016/j.tins.2018.04.009 References 1. Libet, B. et al. (1983) Time of conscious intention to act in relation to onset of cerebral activity (readiness-potential). The unconscious initiation of a freely voluntary act. Brain 106, 623–642 2. Dennett, D.C. and Kinsbourne, M. (1992) Time and the observer: the where and when of consciousness in the brain. Behav. Brain Sci. 15, 183–201 3. Haggard, P. and Eimer, M. (1999) On the relation between brain potentials and the awareness of voluntary movements. Exp. Brain Res. 126, 128–133 4. Shepherd, J. (2012) Free will and consciousness: experimental studies. Conscious. Cogn. 21, 915–927 5. Hart, H.L.A. (2008) Punishment and Responsibility: Essays in the Philosophy of Law, Oxford University Press 6. Dogge, M. et al. (2012) When moving without volition: implied self-causation enhances binding strength between
Science & Society
Revealing the Genetic Instructions for Nervous System Wiring Kevin J. Mitchell1,*,@
Many of the underlying principles were elucidated by Corey Goodman and his colleagues, using the simple nervous systems of grasshopper and fruit fly embryos as models. The embryonic ventral nerve cord of these species is bilaterally symmetric and segmentally repeated, comprising about 200 neurons in each hemisegment. Early work led by Goodman and Michael Bate described the origins and projection patterns of many of these neurons [1]. Further studies using electron microscopy, immunohistochemistry, and targeted cell ablation highlighted the roles in guiding growing axons of cellular interactions with specialised glial cells or with previously projecting axons [2–4].
Why did the axon cross the midline? A 1993 paper by Corey Goodman and colleagues described a genetic screen in fruit flies that pioneered the discovery of conserved families of axon guidance cues and receptors, highlighting fundamental pro- The Midline Screen cesses underlying wiring specificity All of this work laid the foundation for a in the developing nervous system. genetic screen to try to identify the molecGuiding Growing Axons Growing neurons face a daunting task: they must extend their axon along a predefined trajectory through the complex terrain of the developing nervous system, navigating a series of choice points, to
ular cues that guide growing axons and the receptors that determine their responses [5]. This idea was directly inspired by the tremendous success of the genetic screens conducted by Christiane Nüsslein-Volhard and Eric Wieschaus, which had discovered so many of the
Trends in Neurosciences, July 2018, Vol. 41, No. 7
407
fundamental molecules and mechanisms across the genome. These random mutaunderlying early patterning of the fruit fly tions were captured in separate lines by crossing in specific ‘balancer’ chromoembryo [6]. somes that prevent recombination. The The concept behind the screen was to try embryonic progeny derived from interto find genes influencing one simple guid- crossing each line could then be examance decision: whether axons project ined with the expectation that one-quarter across the midline of the ventral nerve cord. of them would be homozygous for the About 90% of neurons in each segment mutant chromosome. This approach tarnormally send an axon across the midline in geted genes on the X chromosome and one of two commissures. These axons on chromosomes 2 and 3, which collecthen make a 90-degree turn to head ante- tively comprise most of the fly genome. riorly or posteriorly in a large longitudinal bundle. The other 10% of axons never Hundreds of mutant lines were recovered cross the midline and just project in the showing defects in the pattern of axonal longitudinal on the same side as their cell projections. These fell into a number of body. The resulting pattern of axons categories, some affecting the longitudiresembles a ladder. Crucially, this pattern nal tracts, others affecting the commiscould be robustly visualised in whole- sures crossing the midline, each in a mount embryos with a specific antibody number of different ways. Through (Figure 1) and even subtle derangements genetic mapping and complementation, from the normal pattern could be detected it was possible to assign different mutations to different genes. The fact that mulunder the dissecting microscope. tiple mutations in individual genes were Mark Seeger, Guy Tear, and Dolores Fer- recovered provided evidence that the res-Marco established over 13 500 screen had achieved saturation: all of mutant lines using a chemical mutagen the genes that could be mutated to give that induces point mutations at random viable embryos with a visible axonal
(A)
(B)
(C)
phenotype had indeed been mutated and screened. The goal of the screen was to identify genes encoding axon guidance cues and receptors, and several were found. However, mutations affecting many other processes, such as embryonic patterning, neurogenesis, or cell fate, can also indirectly result in an aberrant axonal scaffold. A crucial factor in the success of the screen was the ability to analyse mutant lines with a series of other antibodies, revealing defects in these earlier processes in many lines, which could then be excluded from detailed follow up.
Conserved Axon Guidance Molecules Of the mutations with apparently direct effects on axon guidance, two stood out for their specific and reciprocal effects on midline crossing (Figure 1). Mutations in commissureless (comm) resulted in the complete failure of axons to cross the midline. All of the neurons were present and extended axons, but only on their own side, resulting in a ladder with no rungs. Conversely, mutations in roundabout (robo) caused all axons to cross the midline, and not just once: many axons recrossed the midline repeatedly.
These phenotypes suggested that comm might encode a component of an attractive S system, necessary for axons to cross the PC midline, while robo might encode a comIS L ponent of a repulsive system that prevents inappropriate crossing or recrossing. However, double-mutant analysis suggested an alternative model. Double comm;robo mutants look like robo single mutants. Thus, in the absence of robo, removal of comm has no effect: axons can still cross the midline. This suggested that the funcFigure 1. Mutations in commissureless (comm) and roundabout (robo) Disrupt Midline Crossing. tion of the Comm protein might be to The complete axonal scaffold of the Drosophila embryonic ventral nerve cord can be visualised with the antibody repress the Robo system. AC
BP102. (A) Several segments are shown, highlighting the anterior (AC) and posterior (PC) commissures, the longitudinal tracts (L), and the segmental (S) and intersegmental (IS) nerves connecting the central nervous system to the periphery. (B) Phenotype of a comm mutant, where no axons cross the midline. (C) Phenotype of a robo mutant, where all axons cross and recross the midline. Reprinted, with permission, from [5].
408
Trends in Neurosciences, July 2018, Vol. 41, No. 7
When these genes were cloned a few years later, this prediction was borne
out. robo encodes a transmembrane protein of the immunoglobulin superfamily [7]. It was later shown to be one of a trio of related receptors for the secreted protein Slit, which is expressed by specialised glial cells at the midline [8,9]. slit mutations, which were also recovered in the screen, have an even more severe phenotype than robo mutations because of redundancy between robo-1, -2, and -3. Both the Robo and the Slit families are highly conserved and play major roles in axon guidance not just at the midline but in many areas of the developing nervous system, including in the human brain. comm encodes a protein expressed in the endoplasmic reticulum that controls the trafficking of the Robo protein to the cell surface [10]. The selective early expression of Comm in just those neurons that normally cross the midline determines which neurons cross the midline and which do not [11]. This system also dynamically regulates axonal responsiveness, so that axons that have crossed the midline upregulate Robo and subsequently are repelled away from it, ensuring that they only cross once. Recent results from the laboratory of Tom Kidd show that Comm also has an orthologue with similar molecular functions in mammals, mutations in which are implicated in neurological disease [12]. These proteins are all involved in repulsive signalling from the midline but what about attraction? Why do axons head towards the midline in the first place? This similarly depends on a conserved set of molecules: netrins and their receptors of the Unc-40/DCC and Unc-5 families, first discovered in worms [13] and subsequently in vertebrates and flies [14]. Mutations in Netrin genes were not recovered in the midline screen because there are two of them and they act redundantly to attract axons towards the midline. However, mutations in the Unc-40/DCC family receptor, called frazzled in flies, were
identified in the screen, and independently in the laboratory of Yuh-Nung and Lily Jan. These mutations result in fewer axons crossing the midline [15].
11. Keleman, K. (2002) Comm sorts Robo to control axon guidance at the Drosophila midline. Cell 110, 415–427 12. Justice, E.D. (2017) The WAGR syndrome gene PRRG4 is a functional homologue of the commissureless axon guidance gene. PLoS Genet. 13, e1006865 13. Hedgecock, E.M. et al. (1990) The unc-5, unc-6, and unc40 genes guide circumferential migrations of pioneer axons and mesodermal cells on the epidermis in C. elegans. Neuron 4, 61–85
The paper by Seeger et al. helped to pioneer the molecular identification of 14. Davies, A.M. (1994) Neural development. Chemoattractants for navigating axons. Curr. Biol. 4, 1142–1145 axon guidance cues and receptors, most P.A. et al. (1996) frazzled encodes a Drosophila of which were found to be highly con- 15. Kolodziej, member of the DCC immunoglobulin subfamily and is served. In the process it also illustrated required for CNS and motor axon guidance. Cell 87, 197–204 several fundamental principles of general importance. It stands out for the many years of careful descriptive work that preceded it, which laid the foundation for a Series: Seminal Neuroscience Papers genetic screen. In addition, it is testament to the idea that if you know enough about 1978–2017 the system you are investigating, you can let the organism tell you what the under- Science & Society lying processes and important molecules are.
Brain Perfusion and Astrocytes
1 ?[87_TD$IF]?Smurfit Institute of Genetics and Institute of Neuroscience, Trinity College Dublin, Dublin 2, Ireland
*Correspondence: [email protected] (K.J. Mitchell). https://doi.org/10.1016/j.tins.2018.04.008 References 1. Thomas, J.B. et al. (1984) From grasshopper to Drosophila: a common plan for neuronal development. Nature 310, 203–207 2. Goodman, C.S. et al. (1984) Cell recognition during neuronal development. Science 225, 1271–1279 3. Jacobs, J.R. and Goodman, C.S. (1989) Embryonic development of axon pathways in the Drosophila CNS. I. A glial scaffold appears before the first growth cones. J. Neurosci. 9, 2402–2411 4. Klämbt, C. et al. (1991) The midline of the Drosophila central nervous system: a model for the genetic analysis of cell fate, cell migration, and growth cone guidance. Cell 64, 801–815 5. Seeger, M. et al. (1993) Mutations affecting growth cone?guidance in Drosophila: genes necessary for guidance toward or away from the midline. Neuron 10, 409– 426 6. Nüsslein-Volhard, C. and Wieschaus, E. (1980) Mutations affecting segment number and polarity in Drosophila. Nature 287, 795–801 7. Kidd, T. et al. (1998) Roundabout controls axon crossing of the CNS midline and defines a novel subfamily of evolutionarily conserved guidance receptors. Cell 92, 205–215 8. Kidd, T. et al. (1999) Slit is the midline repellent for the Robo receptor in Drosophila. Cell 96, 785–794 9. Brose, K. et al. (1999) Slit proteins bind Robo receptors and have an evolutionarily conserved role in repulsive axon guidance. Cell 96, 795–806 10. Tear, G. et al. (1996) commissureless controls growth cone guidance across the CNS midline in Drosophila and encodes a novel membrane protein. Neuron 16, 501–514
Bruno Cauli1,* and Edith Hamel2,* How can blood rapidly and precisely reach active neurons at a given time and location has remained enigmatic for a long time. A 2003 paper by Zonta et al. suggested key roles for astrocytes in the signaling between neurons and blood vessels. While a consensus on the specific intermediary roles of astrocytes in this process is still evolving, research in the past 15 years has led to a deeper and more refined understanding of the neuro-glio-vascular unit. The brain is an energy-consuming organ that depends on constant glucose and oxygen supply from the blood. The relationship between neuronal activity and local increases in cerebral blood flow, referred to as neurovascular coupling (NVC), was recognized more than a century ago. It is generally considered so precise that modern brain imaging Trends in Neurosciences, July 2018, Vol. 41, No. 7
409